Oncostatin M stimulates excessive extracellular matrix accumulation in a transgenic mouse model of connective tissue disease.
Oncostatin M (OM), a member of the IL-6 gene family, stimulates a variety of functions implicated in wound repair. Transgenic mice that express this cytokine in islet beta-cells develop a connective tissue disorder that typifies excessive healing with severe fibrosis and lymphocytic infiltration. To compare this phenotype with the normal progression of connective tissue disease, we measured the expression patterns of genes encoding proinflammatory cytokines, fibrogenic cytokines, and ECM components by in situ hybridization. To test whether the OM effect was caused by its ability to regulate IL-6, we crossed the OM transgene into IL-6-deficient mice. Our data suggest that the fibrosis in these animals is not a secondary consequence of inflammation, or IL-6 expression, but is a direct effect by OM on extracellular matrix production. In a separate experiment, we observed that OM could regulate vasoactive intestinal peptide gene expression in the neurons that innervate the transgenic pancreas. This nerve healing response, in combination with its fibrogenic activity, suggests that OM functions downstream of inflammation in the wound repair cascade. These transgenic mice represent a useful model in which the fibroproliferative phase of connective tissue disease is uncoupled from inflammation.
Bamber
B
B
Bristol-Myers Squibb Pharmaceutical Research Institute, Seattle, WA 98121, USA.
Reife
R A
RA
Haugen
H S
HS
Clegg
C H
CH
D000818:Animals; D000831:Animals, Newborn; D002417:Cattle; D003240:Connective Tissue Diseases / Q000378:metabolism* / Q000473:pathology; D003433:Crosses, Genetic; D016207:Cytokines / Q000235:genetics / Q000502:physiology; D004195:Disease Models, Animal; D016326:Extracellular Matrix Proteins / Q000235:genetics*; D005355:Fibrosis; D005786:Gene Expression Regulation; D006133:Growth Substances / Q000235:genetics; D015850:Interleukin-6 / Q000235:genetics / Q000502:physiology*; D007515:Islets of Langerhans / Q000378:metabolism; D007963:Leukocytes, Mononuclear; D051379:Mice; D008822:Mice, Transgenic; D053683:Oncostatin M; D010179:Pancreas / Q000276:immunology / Q000294:innervation / Q000378:metabolism / Q000473:pathology*; D010455:Peptides / Q000502:physiology*; D012333:RNA, Messenger / Q000032:analysis; D013564:Sympathetic Nervous System; D019076:Transgenes; D014660:Vasoactive Intestinal Peptide / Q000235:genetics; D014945:Wound Healing / Q000502:physiology
D016207:Cytokines; D016326:Extracellular Matrix Proteins; D006133:Growth Substances; D015850:Interleukin-6; C508352:Osm protein, mouse; D010455:Peptides; D012333:RNA, Messenger; D053683:Oncostatin M; D014660:Vasoactive Intestinal Peptide